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EP0658532A1 - Dihydroxylation asymmétrique catalytique accélérée par un ligand - Google Patents

Dihydroxylation asymmétrique catalytique accélérée par un ligand Download PDF

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Publication number
EP0658532A1
EP0658532A1 EP95200458A EP95200458A EP0658532A1 EP 0658532 A1 EP0658532 A1 EP 0658532A1 EP 95200458 A EP95200458 A EP 95200458A EP 95200458 A EP95200458 A EP 95200458A EP 0658532 A1 EP0658532 A1 EP 0658532A1
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Prior art keywords
dihydroquinidine
osmium
dihydroquinine
olefin
asymmetric
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EP0658532B1 (fr
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Istvan E. Marko
K. Barry Sharpless
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Massachusetts Institute of Technology
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Massachusetts Institute of Technology
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Priority claimed from US07/159,068 external-priority patent/US4871855A/en
Priority claimed from US07/250,378 external-priority patent/US4965364A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C31/18—Polyhydroxylic acyclic alcohols
    • C07C31/20—Dihydroxylic alcohols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/48—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by oxidation reactions with formation of hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/26—Polyhydroxylic alcohols containing only six-membered aromatic rings as cyclic part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C35/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a non-condensed ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C07D453/04—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered

Definitions

  • the organic constituents of animals, microorganisms and plants are made up of chiral molecules, or molecules which exhibit handedness.
  • Enantiomers are stereoisomers or chiral molecules whose configurations (arrangements of constituent atoms) are mirror images of each other; absolute configurations at chiral centers are determined by a set of rules by which a priority is assigned to each substituent and are designated R and S.
  • the physical properties of enantiomers are identical, except for the direction in which they rotate the plane of polarized light: one enantiomer rotates plane-polarized light to the right and the other enantiomer rotates it to the left. However, the magnitude of the rotation caused by each is the same.
  • enantiomers are also identical, with the exception of their interactions with optically active reagents.
  • Optically active reagents interact with enantiomers at different rates, resulting in reaction rates which may vary greatly and, in some cases, at such different rates that reaction with one enantiomer or isomer does not occur. This is particularly evident in biological systems, in which stereo-chemical specificity is the rule because enzymes (biological catalysts) and most of the substrates on which they act are optically active.
  • a mixture which includes equal quantities of both enantiomers is a racemate (or racemic modification).
  • a racemate is optically inactive, as a result of the fact that the rotation of polarized light caused by a molecule of one isomer is equal to and in the opposite direction from the rotation caused by a molecule of its enantiomer.
  • Racemates not optically active compounds, are the products of most synthetic procedures. Because of the identity of most physical characteristics of enantiomers, they cannot be separated by such commonly used methods as fractional distillation (because they have identical boiling points), fractional crystallization (because they are equally soluble in a solvent unless it is optically active) and chromatography (because they are held equally tightly on a given adsorbent, unless it is optically active). As a result, resolution of a racemic mixture into enantiomers is not easily accomplished and can be costly and time consuming.
  • the enzyme catalyst involved in a given chemical reaction ensures that the reaction proceeds asymmetrically, producing only the correct enantiomer (i.e., the enantiomer which is biologically or physiologically functional). This is not the case in laboratory synthesis, however, and, despite the interest in and energy expended in developing methods by which asymmetric production of a desired chiral molecule (e.g., of a selected enantiomer) can be carried out, there has been only limited success.
  • Olefins or alkenes with or without proximal heteroatom-containing functional groups are asymmetrically dihydroxylated, oxyaminated or diaminated using an osmium-catalyzed process which is the subject of the present invention.
  • Chiral ligands which are novel alkaloid derivatives, particularly dihydroquinidine derivatives or dihydroquinine derivatives, useful in the method of the present invention are also the subject of the present invention.
  • the parent alkaloids e.g. quinidine or quinine, can also be used, but the rate of catalysis is slightly slower.
  • an olefin, a selected chiral ligand, an organic solvent, water, an oxidant, an osmium source and, optionally, an additive which accelerates hydrolysis of the osmate intermediate are combined, under conditions appropriate for reaction to occur.
  • the method of ligand-accelerated catalysis of the present invention is useful to effect asymmetric dihydroxylation, asymmetric oxyamination and asymmetric diamination of an olefin of interest.
  • a particular advantage of the catalytic asymmetric method is that only small quantities of osmium catalyst are required.
  • Figure 1 is a schematic representation of asymmetric dihydroxylation via ligand-accelerated catalysis which is carried out by the method of the present invention.
  • Figure 2 is a schematic representation of asymmetric catalytic oxyamination of stilbene which is carried out by the method of the present invention.
  • Figure 3 is a plot of amine concentration vs second-order-rate constant k for the catalytic cis -dihydroxylation of styrene. At point a, no amine has been added. Point a thus represents the rate of the catalytic process in the absence of added amine ligands.
  • Line b represents the rate of the catalytic process in the presence of varying amounts of quinuclidine, a ligand which substantially retards catalysis.
  • Line c represents the rate of the catalytic process in the presence of the dihydroquinidine benzoate derivative 1 represented in Figure 1.
  • Figure 4 is a schematic representation of a proposed mechanism of catalytic olefin dihydroxylation. This scheme shows two diol-producing cycles believed to be involved in the ligand-accelerated catalysis of the present invention.
  • Formula 1 represents an alkaloid-osmium complex
  • formula 2 represents a monoglycolate ester
  • formula 3 represents an osmium(VIII)trioxoglycolate complex
  • formula 4 represents a bisglycolate osmium ester
  • formula 5 represents a dioxobisglycolate.
  • Asymmetric epoxidation has been the subject of much research in the past eight years.
  • the titanium-tartrate epoxidation catalyst is actually a complex mixture of epoxidation catalysts in dynamic equilibrium with each other and that the main species present (i.e., the 2:2 structure) is the best catalyst (i.e., about six times more active than titanium isopropoxide bearing no tartrate).
  • This work also showed that this rate advantage is essential to the method's success because it ensures that the catalysis is channeled through a chiral ligand-bearing species.
  • the new catalytic method of the present invention achieves substantially improved rates and turnover numbers (when compared with previously-available methods), as well as useful levels of asymmetric induction.
  • less osmium catalyst is needed in the method of the present invention than in previously-known methods. As a result, the expense and the possible toxicity problem associated with previously-known methods are reduced.
  • the method of the present invention is exemplified below with particular reference to its use in the asymmetric dihydroxylation of E-stilbene (C6H5CH:CHC6H5) and trans-3-hexene (CH3CH2CH:CHCH2CH3).
  • the method can be generally described as presented below and that description and subsequent exemplification not only demonstrate the dramatic and unexpected results of ligand-accelerated catalysis , but also make evident the simplicity and effectiveness of the method.
  • asymmetric dihydroxylation method of the present invention is represented by the scheme illustrated in Figure 1.
  • asymmetric dihydroxylation of a selected olefin is effected as a result of ligand-accelerated catalysis. That is, according to the method, a selected olefin is combined, under appropriate conditions, with a selected chiral ligand (which in general will be a chiral substituted quinuclidine), an organic solvent, water, an oxidant and osmium tetroxide and, optionally, an acetate compound.
  • a selected chiral ligand which in general will be a chiral substituted quinuclidine
  • a selected olefin, a chiral ligand, an organic solvent, water and an oxidant are combined; after the olefin and other components are combined, OsO4 is added.
  • the resulting combination is maintained under conditions (e.g., temperature, agitation, etc.) conducive for dihydroxylation of the olefin to occur.
  • the olefin, organic solvent, chiral ligand, water and OsO4 are combined and the oxidant added to the resulting combination. These additions can occur very close in time (i.e., sequentially or simultaneously).
  • components of the reaction mixture are combined, to form an initial reaction combination, and olefin is added slowly to it, generally with frequent or constant agitation, such as stirring.
  • olefin is added slowly to it, generally with frequent or constant agitation, such as stirring.
  • organic solvent, chiral ligand, water, OsO4 and the oxidant are combined.
  • the olefin can then be slowly added to the other reactants. It is important that agitation, preferably stirring, be applied during the olefin addition.
  • an additive which accelerates hydrolysis of the osmate ester intermediates can, optionally, be added to the reaction combination.
  • These additives can be soluble, carboxylic acid salts with organic-solubilizing counter-ions (e.g., tetraalkyl ammonium ions).
  • Carboxylate salts which are preferred in the present reaction are soluble in organic media and in organic/aqueous co-solvent systems. For example, tetraethyl ammonium acetate has been shown to enhance the reaction rate and ee of some olefins (Table 3). The additive does not replace the alkaloid in the reaction.
  • Compounds which can be used include benzyltrimethylammoniumacetate, tetramethylammonium acetate and tetraethylammonium acetate.
  • other oxyanion compounds e.g., sulfonates or phosphates
  • the compound can be added to the reaction combination of organic solvent, chiral ligand, water and OsO4 in a reaction vessel, before olefin addition. It is important to agitate (e.g., by stirring) the reaction combination during olefin addition.
  • the additive can also be added to the reaction combination, described above, wherein all of the olefin is added at the beginning of the reaction. In one embodiment, the amount of additive is generally approximately 2 equivalents; in general from about 1 to about 4 equivalents will be used.
  • the process can be run in an organic non-polar solvent such as toluene.
  • an organic non-polar solvent such as toluene.
  • a carboxylate compound which accelerates hydrolysis of the osmate ester intermediates (e.g., tetraethyl- or tetramethyl ammonium acetate) is added.
  • This embodiment is designated the "phase transfer" method.
  • solid olefins which are not soluble, or have limited solubility, in mixtures of acetone/water or acetonitrile/water, are dissolved in toluene and then added slowly a mixture of organic solvent, chiral ligand, water and OsO4.
  • the carboxylate salt serves the dual function of solubilizing the acetate ion in the organic phase where it can promote hydrolysis of the osmate ester, and carrying water associated with it into the organic phase, which is essential for hydrolysis. Higher ee's are obtained with many substrates using this method.
  • boric acid itself i.e., B(OH)3
  • phenylboric acid i.e., Ph-B(OH)2
  • the boric acid is added to the ligand - organic solvent - OsO4 mixture prior to the addition of the olefin.
  • the amount of boric acid added is an amount sufficient to form the borate ester of the diol produced in the reaction.
  • the boric acid hydrolyzes the osmium ester and captures the diols which are generated in the reaction. Neither water nor a soluble carboxylate such as tetraalkyl ammonium carboxylate, is required to hydrolyze the osmium ester in the present borate reaction. Because the presence of water can make the isolation and recovery of water-soluble diols difficult, the addition of a boric acid makes isolation of these diols easier. Especially, in the case of an aryl or alkyl boric acid, it is easy because, in place of the diol, the product is the cyclic borate ester which can be subsequently hydrolyzed to the diol. Iwasawa et al., Chemistry Letters , pp. 1721-1724 (1983). The addition of a boric acid is particularly useful in the slow addition method.
  • the amount of water added to the reaction mixture is an important factor in the present method.
  • the optimum amount of water to be added can be determined empirically and, in general, should be that amount which results in maximum ee. Generally, approximately 10 to 16 equivalents of water can be added, preferably 13 to 14 equivalents should be used.
  • An olefin of interest can undergo asymmetric dihydroxylation according to the present invention.
  • any hydrocarbon containing at least one carbon-carbon double bond as a functional group can be asymmetrically dihydroxylated according to the subject method.
  • the method is applicable to any olefin of interest and is particularly well suited to effecting asymmetric dihydroxylation of prochiral olefins (i.e., olefins which can be converted to products exhibiting chirality or handedness).
  • prochiral olefins i.e., olefins which can be converted to products exhibiting chirality or handedness.
  • the method of the present invention is used to asymmetrically dihydroxylate a chiral olefin, one enantiomer will be more reactive than the other.
  • the chiral ligand used in the asymmetric dihydroxylation method will generally be an alkaloid, or a basic nitrogenous organic compound, which is generally heterocyclic and found widely occurring in nature.
  • alkaloids which can be used as the chiral ligand in the asymmetric dihydroxylation method include cinchona alkaloids, such as quinine, quinidine, cinchonine, and cinchonidine.
  • Examples of alkaloid derivatives useful in the method of the present invention are shown in Table 1. As described in detail below, the two cinchona alkaloids quinine and quinidine act more like enantiomers than like diastereomers in the scheme represented in Figure 1.
  • dihydroquinidine derivatives represented as DHQD
  • dihydroquinine derivatives represented as DHQ
  • DHQD and DHQ have a pseudo-enantiomeric relationship in the present method (DHQD and DHQ are actually diastereomers). That is, they exhibit opposite enantiofacial selection.
  • Such derivatives will generally be esters, although other forms can be used.
  • dihydroquinidine is used as the ligand, delivery of the two hydroxyl groups takes place from the top or upper face (as represented in Figure 1) of the olefin which is being dihydroxylated. That is, in this case direct attack of the re- or re,re- face occurs.
  • the dihydroquinine derivative when the dihydroquinine derivative is the ligand used, the two hydroxyl groups are delivered from the bottom or lower (si- or si,si-face) face of the olefin, again as represented in Figure 1. This is best illustrated by reference to entries 1, 2 and 5 of Table 2. As shown, when DHQD (dihydroquinidine esters) is used, the resulting diol has an R or R,R configuration and when ligand 2 (dihydroquinine esters) is used, the resulting diol has an S or S,S configuration.
  • DHQD dihydroquinidine esters
  • ligand 2 dihydroquinine esters
  • the concentration of the chiral ligand used will range from 0.01 M to 2.0 M.
  • the solution is 0.261M in alkaloid 1 (the dihydroquinidine derivative).
  • the concentrations of both alkaloids represented in Figure 1 are at 0.25M. In this way, the enantiomeric excess resulting under the conditions used is maximized.
  • the amount of chiral ligand necessary for the method of the present invention can be varied as the temperature at which the reaction occurs varies. For example, it is possible to reduce the amount of alkaloid (or other chiral ligand) used as the temperature at which the reaction is carried out is changed. For example, if it is carried out, using the dihydroquinidine derivative, at 0 o C, the alkaloid concentration can be 0.15M. In another embodiment, carried out at 0 o C, the alkaloid concentration was 0.0625M.
  • oxidants i.e., essentially any source of oxygen
  • amine oxides e.g., trimethyl amine oxides
  • tert-butyl hydroperoxide hydrogen peroxide
  • oxygen plus metal catalysts e.g., copper (Cu+-Cu++/O2), platinum (Pt/O2), palladium (Pd/O2)
  • NMO N-methylmorpholine N-oxide
  • NMO is available commercially (e.g., Aldrich Chemicals, 97% NMO anhydrous, or as a 60% solution in water).
  • Osmium will generally be provided in the method of the present invention in the form of osmium tetroxide (OsO4), although other sources (e.g., osmium trichloride anhydrous, osmium trichloride hydrate) can be used. OsO4 can be added as a solid or in solution.
  • OsO4 can be added as a solid or in solution.
  • the osmium catalyst used in the method of the present invention can be recycled, for re-use in subsequent reactions. This makes it possible not only to reduce the expense of the procedure, but also to recover the toxic osmium catalyst.
  • the osmium catalyst can be recycled as follows: Using reduction catalysts (e.g., Pd-C), the osmium VIII species is reduced and adsorbed onto the reduction catalyst. The resulting solid is filtered and resuspended.
  • NMO or an oxidant
  • the alkaloid and the substrate (olefin) are added, with the result that the osmium which is bound to the Pd/C solid is reoxidized to OsO4 and re-enters solution and plays its usual catalytic role in formation of the desired diol.
  • This procedure (represented below) can be carried out through several cycles, thus re-using the osmium species.
  • the palladium or carbon can be immobilized, for example, in a fixed bed or in a cartridge.
  • an olefin such as recrystallised trans-stilbene (C6H5CH:CHC6H5)
  • a chiral ligand e.g., p-chlorobenzoyl hydroquinidine
  • acetone e.g., acetone
  • water and NMO e.g., acetone
  • the components can be added sequentially or simultaneously and the order in which they are combined can vary.
  • the resulting combination is cooled (e.g., to approximately 0 o C in the case of trans-stilbene); cooling can be carried out using an ice-water bath.
  • OsO4 is then added (e.g., by injection), in the form of a solution of OsO4 in an organic solvent (e.g., in toluene). After addition of OsO4, the resulting combination is maintained under conditions appropriate for the dihydroxylation reaction to proceed.
  • a chiral ligand e.g., dihydroquinidine 4-chlorobenzoate
  • NMO e.g., NMO
  • acetone e.g., water
  • OsO4 as a 5M toluene solution
  • the components can be added sequentially or simultaneously and the order in which they are combined can vary.
  • the resulting combination is cooled (e.g., to approximately 0 o C); cooling can be carried out using an ice-water bath. It is particularly preferred that the combination is agitated (e.g., stirred).
  • an olefin e.g., trans-3-hexene
  • is added slowly e.g., by injection.
  • the optimum rate of addition (i.e., giving maximum ee), will vary depending on the nature of the olefinic substrate.
  • the olefin was added over a period of about 16-20 hours.
  • the mixture can be stirred for an additional period of time at the low temperature (1 hour in the case of trans-3-hexene).
  • the slow-addition method is preferred as it results in better ee and faster reaction times.
  • a compound which accelerates hydrolysis of the osmate ester intermediates e.g., a soluble carboxylate salt, such as tetraethylammonium acetate
  • a compound which accelerates hydrolysis of the osmate ester intermediates e.g., a soluble carboxylate salt, such as tetraethylammonium acetate
  • the compound (approximately 1-4 equiv.) can be added to the mixture of chiral ligand, water, solvent, oxidant and osmium catalyst and olefin, or prior to the addition of olefin, if the olefin slow-addition method is used.
  • the diol-producing mechanistic scheme which is thought to operate when the slow-addition of olefin method is used is represented in Figure 4.
  • the key intermediate is the osmium (VIII) trioxoglycolate complex, shown as formula 3 in Figure 4, which has the following general formula: wherein L is a chiral ligand and wherein R1, R2, R3 and R4 are organic functional groups corresponding to the olefin.
  • R1, R2, R3 and R4 could be alkyl, aryl, alkoxy, aryloxy or other organic functional groups compatible with the reaction process. Examples of olefins which can be used, and their functional groups, are shown on Table 2 hereinabove.
  • This complex occupies the pivotal position at the junction between the two cycles, and determines how diol production is divided between the cycles.
  • Reduced ee is just part of the counterproductivity or turning on the second cycle; reduced turnover is the other liability.
  • the bisosmate esters (formula 4, Figure 4) are usually slow to reoxidize and hydrolyze, and therefore tend to tie up the catalyst. For example, 1-phenylcyclohexene took 7 days to reach completion under the original conditions (the 8% ee cited above). With slow addition of the olefin, the oxidation was complete in one day and gave the diol in 95% yield and 78% ee (entry 3, Table 3).
  • the maximum ee obtainable in the catalytic process is determined by the addition of the alkaloid osmium complex (formula 1, Figure 4) to the olefin (i.e., the first column in Table 3).
  • stoichiometric additions can be used to enable one to determine the ee-ceiling which can be reached or approached in the catalytic process if the hydrolysis of 3 ( Figure 4) can be made to dominate the alternative reaction with a second molecule of olefin to give 4 ( Figure 4).
  • temperature also effects the ee.
  • raising the temperature can often increase it.
  • diisopropyl ethylene gave 46% ee at 0°C and 59% ee at 25°C (24h slow addition time in both cases).
  • the rate of hydrolysis of the osmium trioxoglycolate intermediate is apparently more temperature dependent than the rate of its reaction with olefin.
  • the reaction mixture When the olefin addition rate is slow enough, the reaction mixture remains yellow-orange (color of 1, Figure 4); when the rate is too fast, the solution takes on a blackish tint, indicating that the dark-brown-to-black bisglycolate complex (4, Figure 4) is being generated; 3) If the ceiling ee is not reached after steps 1 and 2, slow addition plus tetraalkyl ammonium acetate (or other compound which assists hydrolysis of the osmate ester intermediate) at 0°c can be used; 4) slow addition plus a soluble carboxylate salt, such as tetraalkyl ammonium acetate at room temperature can also be used. For all these variations, it is preferable that the mixture is agitated (e.g., stirred) for the entire reaction period.
  • agitated e.g., stirred
  • the method of the present invention can be carried out over a wide temperature range and the limits of that range will be determined, for example, by the limit of the organic solvent used.
  • the method can be carried out, for example, in a temperature range from about 40°c to about -30°C.
  • Concentrations of individual reactants e.g., chiral ligand, oxidant, etc.
  • concentration of individual reactants can be varied as the temperature at which the method of the present invention is carried out.
  • the saturation point e.g., the concentration of chiral ligand at which results are maximized
  • the organic solvent used in the present method can be, for example, acetone, acetonitrile, THF, DME, ethanol, methanol, pinacolone, tert butanol or a mixture of two or more organic solvents.
  • styrene was combined with a chiral ligand (DHQD), acetone, water and NMO and OsO4.
  • DHQD chiral ligand
  • acetone acetone
  • water water
  • NMO chiral ligand
  • OsO4 chiral ligand
  • the plot of amine concentration vs second-order-rate-constant K for the catalytic cis -dihydroxylation of styrene is represented in Figure 3.
  • the kinetic data of Figure 3 clearly shows the dramatic effect of ligand-accelerated catalysts achieved by use of the method of the present invention.
  • the limiting step is the same in both processes and consists of the initial addition reaction forming the osmate ester (2, Figure 4).
  • the rate acceleration in the presence of the alkaloid is accounted for by facilitation of the initial osmylation step.
  • the strikingly opposite effects of quinuclidine and DHQD on the catalysis can be related to the fact that although quinuclidine also accelerates the addition of osmium tetroxide to olefins, it binds too strongly to the resulting osmium(VI) ester intermediate and inhibits catalyst turnover by retarding the hydrolysis/reoxidation steps of the cycle.
  • the alkaloid appears to achieve a balancing act which renders it near perfect for its role as an accelerator of the dihydroxylation catalysis.
  • the method of the present invention has been applied to a variety of olefins.
  • the face selection rule described above has been shown to apply (with reference to the orientation of the olefin as represented in Figure 1). That is, in the case of the asymmetric dihydroxylation reaction in which the dihydroquinidine derivative is the chiral ligand, attack occurs on the re-or re,re- face) and in the case in which the dihydroquinine derivative is the chiral ligand, attack occurs on the si- or si,si- face.
  • the method of the present invention is effective in bringing about catalytic asymmetric dihydroxylation; in all cases, the yield of the diol was 80-95%, and with the slow-addition modification, most olefins give ee's in the rage of 40-90%.
  • the present method can be used to synthesize chiral intermediates which are important building blocks for biologically active chiral molecules, such as drugs.
  • the present method was used to produce an optically pure intermediate used in synthesizing the drug diltiazum (also known as cardizem).
  • the reaction is shown in the following scheme:
  • the method of the present invention is also useful to effect asymmetric vicinal oxyamination of an olefin, and may be useful for asymmetric vicinal diamination.
  • an amino derivative is used as an amino transfer agent and as an oxidant.
  • the olefin to be modified, an organic solvent, water, a chiral ligand, an amino derivative and an osmium-containing compound are combined and the combination maintained under conditions appropriate for the reaction to occur.
  • the amino derivative can be, for example, an N-chlorocarbamate or chloroamine T.
  • OsO4 (4.25 mL of a solution prepared using 0.120g OsO4/mL toluene; 0.002 Mol%; 0.002 eq.) was injected.
  • the bottle was shaken and placed in a refrigerator at ca. 4 o C with occasional shaking.
  • a dark purple color developed and was slowly replaced by a deep orange one; the heterogeneous reaction mixture gradually became homogeneous and at the end of the reaction, a clear orange solution was obtained.
  • the reaction can be conveniently monitored by TLC (silica gel; CH2Cl2; disappearance of the starting material at a defined Rf).
  • the crude oil was dissolved in ethyl acetate (750 mL), extracted three times with 500 ml. portions of 2.0 M HCl, once with 2.0 K NaOH, dried over Na2SO4 and concentrated in vacuo to leave 190 g (89%) of the crude diol as a pale yellow solid.
  • Methylene chloride was added (500 mL) and the pH adjusted to 10-11 using more 2.0M NaOH (about 500 mL).
  • the aqueous layer was separated, extracted twice with methylene chloride (2x300 mL) and the combined organic layers were dried over Na2SO4.
  • the solvent was removed in vacuo to provide the alkaloid as a yellow foam.
  • the crude alkaloid was dissolved in ether (1000 mL), cooled to 0 o C (ice-bath) and treated with dry HCl until acidic pH (about 1-2).
  • the faint yellow precipitate of p-chlorobenzoylhydroquinidine hydrochloride was collected by filtration and dried under high vacuum (0.01mm Hg).
  • Asymmetric dihydroxylation of stilbene was carried out as described in Example 1, except that 1.2 equivalents of NMO, as a 62% wt. solution in water, were used.
  • the crude dihydroquinidine p-chlorobenzoate (1) was dissolved in 1L of ether, cooled to 0 o C and HCl gas was bubbled into the solution until a pH of 1-2 was obtained using wet pH paper.
  • the pale yellow precipitate of 1 as the hydrochloride salt was collected by filtration and dried under high vacuum (0.01mm Hg).
  • the phenylborate was dissolved into acetone (3 mL) and 1,3-propandiol (0.5 mL), and the resulting mixture was stood for 2 h at room temperature.
  • the solvent was evaported under reduced pressure, and the residual oil was subjected to column chromatography on silica gel (5g, elution with hexaneethyl acetate, 2:1 V / V , R f 0.10) to afford 48.6 mg (70%) of the diol.
  • the invention relates to a method of ligand-accelerated catalysis, comprising combining an olefin, a chiral ligand, an organic solvent, water, an oxidant and an osmium catalyst, under conditions appropriate for reaction to occur.
  • Also embraced by the invention is a method of osmium-catalyzed asymmetric addition to an olefin, comprising combining the olefin, a chiral ligand, an organic solvent, water, an oxidant and an osmium-containing catalyst, under conditions appropriate for asymmetric addition to the olefin to occur.
  • the chiral ligand may be an alkaloid or an alkaloid derivative
  • the organic solvent may be acetone
  • the oxidant may be selected from the group consisting of amine oxides, hydrogen peroxide, tert-butyl hydroperoxide, a metal catalyst/oxygen combination N-chloro-N-metallo carbamates and chloramine-T
  • the osmium-containing compound may be osmium tetroxide.
  • the method may further comprise adding a soluble carboxylate salt, e.g. tetraalkyl ammonium acetate.
  • a soluble carboxylate salt e.g. tetraalkyl ammonium acetate.
  • the invention also embraces a method of osmium-catalyzed asymmetric dihydroxylation of an olefin, comprising combining the olefin, a selected chiral ligand, acetone, water, an amine oxide and an osmium-containing compound in sufficient quantity to provide a catalytic amount of osmium, under conditions appropriate for asymmetric dihydroxylation to occur.
  • the chiral ligand may be an alkaloid or an alkaloid derivative
  • the amine oxide may be N-methylmorpholine N-oxide
  • the osmium-containing compound may be osmium tetroxide.
  • the alkaloid derivative may be a dihydroquinidine derivative or a dihydroquinine derivative.
  • the method may further comprise adding a tetraalkyl ammonium carboxylate, e.g. tetraalkyl ammonium acetate.
  • a tetraalkyl ammonium carboxylate e.g. tetraalkyl ammonium acetate.
  • the invention also relates to a method of osmium-catalyzed asymmetric dihydroxylation of an olefin, comprising combining the olefin, a selected chiral ligand, an organic solvent, a boric acid derivative, an amine oxide and an osmium-containing compound in sufficient quantity to provide a catalytic amount of osmium, under conditions appropriate for asymmetric dihydroxylation to occur.
  • the chiral ligand may be an alkaloid or an alkaloid derivative
  • the amine oxide may be N-methyl morpholine N-oxide
  • the osmium-containing compound may be osmium tetroxide.
  • the alkaloid derivative may be a hydroquinidin derivative or a dihydroquinine derivative.
  • the organic solvent may be dichloromethane or chloroform.
  • the invention also covers an osmium-catalyzed method of asymmetric dihydroxylation of an olefin, comprising the steps of:
  • the cinchona alkaloid derivative may be a dihydroquinidine derivative or a dihydroquinine derivative
  • the amine oxide may be N-methyl morpholine N-oxide
  • the osmium-containing compound may be osmium tetroxide.
  • an osmium-catalyzed method of producing an asymmetrically dihydroxylated olefin comprising:
  • Also embraced by the invention is an osmium-catalyzed method of asymmetric oxyamination of an olefin, comprising combining the olefin, a chiral ligand, an organic solvent, water, a metallochloramine derivative and an osmium-containing catalyst, under conditions appropriate for asymmetric oxyamination to occur.
  • the chiral ligand may be an alkaloid or an alkaloid derivative.
  • the invention also relates to an osmium-catalyzed method of asymmetric diamination of an olefin, comprising combining the olefin, a chiral ligand, an organic solvent, a metallochloramine derivative, an amine, and an osmium-containing catalyst, under conditions appropriate for asymmetric diamination to occur.
  • the chiral ligand may be an alkaloid or an alkaloid derivative.
  • the invention also relates to a method of osmium-catalyzed asymmetric addition to an olefin, comprising combining the olefin, an osmium-alkaloid catalyst complex, the complex comprising an osmium-containing composition and an alkaloid or derivative thereof; an organic solvent; water; and an oxidant, under conditions appropriate for asymmetric addition to the olefin to occur.
  • Also contemplated by the invention is an osmium-catalyzed method of asymmetric dihydroxylation of an olefin, comprising the steps of:
  • the alkaloid may be cinchona alkaloid
  • the amine oxide may be N-methyl morpholine N-oxide
  • the osmium-containing compound may be osmium tetroxide.
  • the method of the invention may further comprise adding a soluble carboxylate salt, e.g. tetraalkyl ammonium acetate.
  • a soluble carboxylate salt e.g. tetraalkyl ammonium acetate.
  • the method of the invention may further comprise dissolving the olefin in an organic solvent prior to slow addition of the olefin in (c).
  • an osmium-catalyzed method of asymmetric dihydroxylation of an olefin comprising the steps of:
  • the alkaloid may be a cinchona alkaloid
  • the amine oxide may be N-methylmorpholine N-oxide
  • the osmium-containing compound may be osmium tetroxide.
  • the method of the invention may further comprise dissolving the olefin in an organic solvent prior to slow addition of the olefin in (c).
  • the invention also contemplates an osmium-catalyzed method for producing an asymmetrically dihydroxylated olefin, comprising:
  • the cinchona alkaloid derivative may be a dihydroquinidine derivative or a dihydroquinine derivative and the tetraalkyl ammonium compound may be tetraethylammonium acetate.
  • the method of the invention may further comprise dissolving the olefin in an organic solvent prior to slow addition of the olefin in (b).
  • alkaloid derivative selected from the group consisting of:
  • the invention in another aspect, relates to a dihydroquinidine ester of the formula wherein R' is p-chlorobenzoyl and Ar is Also covered by the invention is a dihydroquinine ester of the formula wherein R' is p-chlorobenzoyl and Ar is
  • the invention also contemplates an osmium-alkaloid catalyst complex comprising osmium tetroxide and an alkaloid derivative, the alkaloid derivative selected from the group consisting of:
  • the invention also embraces an osmium-dihydroquinine ester complex of the formula: wherein R' is p-chlorobenzoyl and Ar is Also covered by the invention is an osmium (VIII) trioxoglycolate complex formed during asymmetric dihydroxylation of an olefin, of the formula: wherein L is a chiral ligand and wherein R1, R2, R3 and R4 are organic functional groups corresponding to the olefin.
  • the chiral ligand may be a cinchona alkaloid derivative.
  • the cinchona alkaloid derivative of the complex of the invention may be selected from the group consisting of:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Catalysts (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Epoxy Compounds (AREA)
EP95200458A 1988-01-11 1989-01-10 Dihydroxylation asymmétrique catalytique accélérée par un ligand Expired - Lifetime EP0658532B1 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US14269288A 1988-01-11 1988-01-11
US142692 1988-01-11
US159068 1988-02-23
US07/159,068 US4871855A (en) 1988-01-11 1988-02-23 Ligand-accelerated catalytic asymmetric dihydroxylation using dihydroquinidine and dihydroquinidine esters as ligands
US250378 1988-09-28
US07/250,378 US4965364A (en) 1988-02-23 1988-09-28 Ligand-accelerated catalytic asymmetric dihydroxylation
EP89901900A EP0395729B1 (fr) 1988-01-11 1989-01-10 Dihydroxylation asymetrique catalytique acceleree par un ligand

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EP89901900.4 Division 1989-01-10

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US5227543A (en) * 1988-01-11 1993-07-13 Massachusetts Institute Of Technology Facilitation of turnover in the ADH by additives which catalyze the hydrolysis of the OS(VI) glycolate esters
EP0543969A1 (fr) * 1991-05-13 1993-06-02 Massachusetts Institute Of Technology Ligands chiraux heterocycliques et procede de dihydroxylation asymetrique et catalytique d'olefines
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CN102531911A (zh) * 2011-12-22 2012-07-04 浙江工业大学 手性二环类化合物及其不对称合成方法
CN102531911B (zh) * 2011-12-22 2016-02-17 浙江工业大学 手性二环类化合物及其不对称合成方法

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DE68928969T2 (de) 1999-12-16
DE68928969D1 (de) 1999-05-12
DE68924418D1 (de) 1995-11-02
JPH03503885A (ja) 1991-08-29
DE68924418T2 (de) 1996-03-28
EP0395729B1 (fr) 1995-09-27
ATE178578T1 (de) 1999-04-15
ATE128449T1 (de) 1995-10-15
JP2001192383A (ja) 2001-07-17
EP0658532B1 (fr) 1999-04-07
WO1989006225A1 (fr) 1989-07-13
CA1338314C (fr) 1996-05-07
EP0395729A1 (fr) 1990-11-07
JP3153540B2 (ja) 2001-04-09

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